Neodymium di(2-ethylhexyl) phosphate

Endpoint summary

Description of key information

- Skin irritation: not irritating
- Eye irritation: not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 1 September 2006 to 20 April 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: the study was performed according to internationally recognised guidelines and GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

the temperature and relative humidity sometimes outside of the target ranges (this minor deviation was not considered to have compromised the validity or integrity of the study).

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

see higher

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

yes

Remarks:

see higher

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Grimaud frères selection S.A.S., La Corbière, Roussay, France
- Age at study initiation: on the day of treatment, the animals were 2 to 4 months old
- Weight at study initiation: on the day of treatment, the animals had a mean body weight of 2.8 ± 0.2 kg
- Housing: the animals were housed individually in Pajon cages (50 cm x 57 cm x 75 cm)
- Diet: free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France)
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3°C
- Humidity: 30 to 70%
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: from 12 September 2006 (day of treatment of the first animal) to 17 September 2006 (end of the observation period)

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 500 mg

Duration of treatment / exposure:

The test item was first evaluated on a single animal. The durations of exposure were 3 minutes, 1 hour and 4 hours.
Since the test item was neither severely irritant nor corrosive on this first animal, it was then applied for 4 hours simultaneously to two other animals.

Observation period:

72 hours

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: anterior left flank (application for 3 minutes), anterior right flank (application for 1 hour) or posterior right flank (application for 4 hours)
- % coverage: approximately 6 cm2
- Type of wrap if used: gauze pad held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing: yes (any residual test item was wiped off by means of a dry cotton pad
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Erythema and eschar formation:
. no erythema -> 0
. very slight erythema (barely perceptible) -> 1
. well-defined erythema -> 2
. moderate to severe erythema -> 3
. severe erythema (beet redness) to slight eschar formation (injuries in depth) -> 4
Oedema formation
. no oedema -> 0
. very slight oedema (barely perceptible) -> 1
. slight oedema (edges of area well-defined by definite raising) -> 2
. moderate oedema (raised approximately 1 millimetre) -> 3
. severe oedema (raised more than 1 millimetre and extending beyond area of exposure) -> 4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: NOt applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

After a 3-minute and a 1-hour exposure (one animal):
No cutaneous reactions were observed.

After a 4-hour exposure (three animals):
A very slight erythema (grade 1) was noted in 2/3 animals on day 1 only.
No other cutaneous reactions were observed thereafter.
Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for edema.

Table 1: Individual cutaneous examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours)

 

Rabbit number	Dermal irritation	Scores				Mean irritation score (1)	Interpretation (+) or (-)
		1h	24h	48h	72h
646	Erythema Edema Other	0 0 *	0 0 *	0 0 *	0 0 *	0.0 0.0	(-) (-)
608	Erythema Edema Other	1 0 *	0 0 *	0 0 *	0 0 *	0.0 0.0	(-) (-)
609	Erythema Edema Other	1 0 *	0 0 *	0 0 *	0 0 *	0.0 0.0	(-) (-)

(1) mean of scores on days 2, 3 and 4

(+) = irritant according to E.E.C. criteria

(-) = non-irritant according to E.E.C. criteria

* = none

Interpretation of results:

GHS criteria not met

Conclusions:

Neodymium tris(di-2-ethylhexylphosphate) is not considered to be a skin irritant in the rabbit.

Executive summary:

In a primary dermal irritation study performed according to OECD 404, EC B.4, US/EPA/OPPTS 870.2500 and GLP (CIT report No. 32230 TAL, 2007), scored as validity 1 according to Klimisch criteria, 3 male New Zealand White rabbits were dermally exposed to 0.5 g of neodymium tris(di-2-ethylhexylphosphate) applied on the skin of flanks and maintained under semi-occlusive dressing for 4 hours. Animals then were observed for 72 hours. Irritation was scored 1, 24, 48 and 72 h after removal of the dressing by calculating dermal irritation scores, based on the grading of cutaneous erythema and edema.

 

After a 3-minute and a 1-hour exposures (one animal), no cutaneous reactions were observed.

After a 4-hour exposure (three animals), a very slight erythema was noted in 2/3 animals on day 1 only. No other cutaneous reactions were observed thereafter.

Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for edema.

The test substance was considered as non-irritant to the skin. No classification for skin irritation is warranted based on the observed cutaneous reactions following a 4-hour exposure, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.

This study is classified as acceptable. It satisfies international guideline requirements for acute dermal irritation or corrosion.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 1 September 2006 to 20 April 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: the study was performed according to internationally recognised guidelines and GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

the temperature and relative humidity sometimes outside of the target ranges (this minor deviation was not considered to have compromised the validity or integrity of the study)

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

see higher

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

yes

Remarks:

see higher

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Grimaud frères selection S.A.S., La Corbière, Roussay, France
- Age at study initiation: on the day of treatment, the animals were 2 to 4 months old
- Weight at study initiation: on the day of treatment, the animals had a mean body weight of 3.0 ± 0.2 kg
- Housing: individually in Pajon cages (50 cm x 57 cm x 75 cm)
- Diet: free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France)
- Water: drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3°C
- Humidity: 30 to 70%
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12hrs dark / 12hrs light)

IN-LIFE DATES: from 19 September 2006 (day of treatment of the first animal) to 24 September 2006 (end of the observation period)

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount: 100 mg
- Concentration: undiluted

Duration of treatment / exposure:

Single conjunctival instillation

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM:
Ocular reactions were scored according to the following numerical scale:
CONJUNCTIVAL LESIONS AND DISCHARGE:
> Chemosis (lids and/or nictitating membranes)
. no swelling = 0
. any swelling above normal (includes nictitating membranes) = 1
. obvious swelling with partial eversion of lids = 2
. swelling with lids about half-closed = 3
. swelling with lids more than half-closed = 4
> Redness (refers to palpebral and bulbar conjunctivae, cornea and iris)
. blood vessels normal = 0
. a number of blood vessels definitely hyperemic (injected) = 1
. diffuse, crimson colour, individual vessels not easily discernible = 2
. diffuse, beefy red = 3
> Discharge
. absence of discharge = 0
. slight discharge (does not include small amounts normally found in inner canthus) = 1
. discharge with moistening of lids and hairs adjacent to lids = 2
. discharge with moistening of lids and hairs on wide area around the eye = 3
IRIS LESIONS:
. normal = 0
. markedly deepened rugae, congestion, swelling, moderate circum-corneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) = 1
. no reaction to light, haemorrhage, gross destruction (any or all of these) = 2
CORNEAL LESIONS:
> Degree of opacity (area most dense taken for reading)
. no ulceration or opacity = 0
. scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible = 1
. easily discernible translucent area, details of iris slightly obscured = 2
. nacreous areas, no details of iris visible, size of pupil barely discernible = 3
. opaque cornea, iris not discernible through the opacity = 4
> Area of opacity
. one quarter (or less) but not zero = 1
. greater than one quarter but less than a half = 2
. greater than one half but less than three quarters = 3
. greater than three quarters up to whole area = 4
Any other lesions observed were noted.

TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: Not applicale

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

other: Not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 24 h

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

A slight chemosis (grade 1) was observed in all the animals on days 1.
A slight redness of the conjunctiva (grade 1) was noted in all the animals at 1 hours after treatment; it persisted at time point 24 hours in 2/3 animals.
No other ocular reactions were recorded during the study.

Other effects:

Residual test item was noted in all the animals on day 1 only.

Table 1: Individual ocular examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours)

 

Rabbit number	Region of the eye	Description of ocular reactions	Scores				Mean irritation score (1)	Interpretation (+) or (-)
			1h	24h	48h	72h
646	Conjunctivae	Chemosis Redness Discharge	1 1 0	1 0 0	0 0 0	0 0 0	0.3 0.0 0.0	(-) (-)
	Iris		0	0	0	0	0.0	(-)
	Corneal opacity	Intensity Area	0 0	0 0	0 0	0 0	0.0 0.0	(-)
	Other		Su	*	*	*
	Fluorescein		/	U	/	/
608	Conjunctivae	Chemosis Redness Discharge	1 1 0	1 1 0	0 0 0	0 0 0	0.3 0.3	(-) (-)
	Iris		0	0	0	0	0.0	(-)
	Corneal opacity	Intensity Area	0 0	0 0	0 0	0 0	0.0 0.0	(-)
	Other		Su	*	*	*
	Fluorescein		/	U	/	/
609	Conjunctivae	Chemosis Redness Discharge	1 1 0	1 1 0	0 0 0	0 0 0	0.3 0.3	(-) (-)
	Iris		0	0	0	0	0.0	(-)
	Corneal opacity	Intensity Area	0 0	0 0	0 0	0 0	0.0 0.0	(-)
	Other		Su	*	*	*
	Fluorescein		/	U	/	/

(1) mean of scores on days 2, 3 and 4

(+) = irritant according to E.E.C. criteria

(-) = non-irritant according to E.E.C. criteria

* = none

Su = residual test item

U = fluorescein batch No. K 742

/ = fluorescein not used

Interpretation of results:

GHS criteria not met

Conclusions:

Neodymium tris(di-2-ethylhexylphosphate) is not considered to be an eye irritant in the rabbit according to EU criteria.

Executive summary:

In a primary eye irritation study performed according to OECD 405, EC B.5 ,US/EPA/OPPTS 870.2400 and GLP (CIT report No.32231 TAL, 2007), scored as validity 1 according to Klimisch criteria, 100 mg of neodymium tris(di-2-ethylhexylphosphate) were instilled into the conjunctival sac of the left eye of 3 male New Zealand White rabbits. Exposed eyes were not rinsed. Animals then were observed for 72 hours. Irritation was scored 1, 24, 48 and 72 hours after instillation by calculating ocular irritation scores, based on the grading of conjunctiva, iris and cornea scores.

A slight chemosis was observed in all the animals on days 1,  from 1 hour up to 24 hours after treatemnt.

A slight redness of the conjunctiva was noted in all the animals 1h after treatement; it persisted up to 24 hours in 2/3 animals.

Residual test item was noted in all the animals on day 1 only.

No other ocular reactions were recorded during the study.

Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.3 and 0.3 for chemosis, 0.0, 0.3 and 0.3 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.

 

No classification for eye irritation is warranted based on the ocular reactions observed during 72 hours after exposure, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.

 

This study is classified as acceptable. It satisfies the international guideline requirements for acute eye irritation or corrosion.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Neodymium tris(di-2-ethylhexylphosphate) was tested in one dermal irritation study and one eye irritation study, both performed according to internationally recognised guidelines and GLP, scored as validity 1 according to Klimisch criteria, and considered as key studies acceptable for the assessment.

In a primary dermal irritation study performed according to OECD 404, EC B.4, US/EPA/OPPTS 870.2500 and GLP (CIT report No. 32230 TAL, 2007), scored as validity 1 according to Klimisch criteria, 3 male New Zealand White rabbits were dermally exposed to 0.5 g of neodymium tris(di-2-ethylhexylphosphate) applied on the skin of flanks and maintained under semi-occlusive dressing for 4 hours. Animals then were observed for 72 hours. Irritation was scored 1, 24, 48 and 72 h after removal of the dressing by calculating dermal irritation scores, based on the grading of cutaneous erythema and edema.

After a 3-minute and a 1-hour exposures (one animal), no cutaneous reactions were observed.

After a 4-hour exposure (three animals), a very slight erythema was noted in 2/3 animals on day 1 only. No other cutaneous reactions were observed thereafter.

Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.0 for erythema and 0.0, 0.0 and 0.0 for edema.

According to these results, the test item is not classified as a skin irritant according to EU criteria.

 

 

In a primary eye irritation study performed according to OECD 405, EC B.5, US/EPA/OPPTS 870.2400 and GLP (CIT report No.32231 TAL, 2007), scored as validity 1 according to Klimisch criteria, 100 mg of neodymium tris(di-2-ethylhexylphosphate) were instilled into the conjunctival sac of the left eye of 3 male New Zealand White rabbits. Exposed eyes were not rinsed. Animals then were observed for 72 hours. Irritation was scored 1, 24, 48 and 72 hours after instillation by calculating ocular irritation scores, based on the grading of conjunctiva, iris and cornea scores.

 

A slight chemosis was observed in all the animals on days 1 and 2.

A slight redness of the conjunctiva was noted in all the animals on day 1; it persisted on day 2 in 2/3 animals.

Residual test item was noted in all the animals on day 1 only.

No other ocular reactions were recorded during the study.

Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.3 and 0.3 for chemosis, 0.0, 0.3 and 0.3 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.

 

According to these results, the test item is not classified as an eye irritant according to EU criteria.

Justification for classification or non-classification

Based on the results of these studies, neodymium tris(di-2-ethylhexylphosphate) was considered as non-irritant to the skin and to the eye. No classification for skin and eye irritation is warranted, according to the criteria of Annex VI Directive 67/548/EEC or UN/EU GHS.